Prion Diseases

Key Features

• Proteinaceous infectious particles or prions

• Prions induce conformational change ("misfolding") of normal brain protein (prion protein; PrP)

• Prion disease can be hereditary, sporadic, and transmissible

• Hereditary disorders cause

  • Familial Creutzfeldt–Jakob disease (fCJD)

  • Gerstmann-Sträussler-Scheinker syndrome (GSS)

  • Fatal familial insomnia (FFI)

  • PrP systemic amyloidosis

• Sporadic Creutzfeldt-Jakob disease (sCJD)

  • Accounts for approximately 85% of cases

  • No known cause

• Transmissible prion disease is only described for kuru and Creutzfeldt-Jakob disease in its iatrogenic (iCJD) and variant (vCJD) form

• Iatrogenic transmission of CJD is associated with

  • Prion contaminated human corneas

  • Dura mater grafts

  • Pituitary-derived growth hormone, gonadotropins

  • Stereotactic electroencephalography electrodes and neurosurgical instruments

• Kuru is now rare

• vCJD (bovine spongiform encephalopathy [BSE] or "mad cow disease")

  • Characterized by its bovine-to-human transmission through ingestion of meat from cattle infected with BSE

  • There is no animal-to-animal spread of BSE and milk and its derived products are not considered to be infected

  • Secondary transmission due to blood transfusions from asymptomatic donors are reported in the United Kingdom

  • Rare in the United States; between 1996 and 2015, only 4 cases reported in the United States and 19 in Canada. Of the US reported cases, none acquired the disease locally (2 of them acquired the infection in the United Kingdom and 1 in Saudi Arabia).

Clinical Findings

• Both sCJD and fCJD usually present in the sixth or seventh decade of life, whereas the iCJD form tends to occur in a much younger population

• Clinical features of these three forms of disease usually involve

  • Mental deterioration (dementia, behavioral changes, loss of cortical function) progressive over several months

  • Myoclonus

  • Extrapyramidal (hypokinesia) and cerebellar manifestations (ataxia, dysarthria)

• Finally, coma ensues, usually associated with an akinetic state and less commonly decerebrate/decorticate posturing

• Kuru

  • Early stage of tremors, ataxia and postural instability followed by involuntary movements (myoclonus, fasciculations and choreathetosis)

  • Final stage of dementia

• GSS

  • Rare inherited autosomal dominant (rarely sporadic) disorder that occurs in kindred

  • Typically causes a disruption of the circadian sleep-activity pattern leading to insomnia, hallucinations, behavioral changes, motor disturbance and rarely dementia

• FFI is the only prior disease associated with endocrine disorders and dysautonomia

Diagnosis

• Detection of 14-3-3 protein in the cerebrospinal fluid is helpful for the diagnosis of sCJD but not in vCJD and fCJD

• A blood-based assay and a polymerase chain reaction (PCR) in cerebrospinal fluid show some promising results in the diagnosis of vCJD with high specificity but 71% sensitivity; further evaluation is under way

• EEG

  • In CJD, typically shows a pattern of paroxysms with high voltages and slow waves

  • In sCJD, typically shows a pattern of paroxysms with high voltages and slow waves

  • In vCJD, is diffusely abnormal but nondiagnostic

• MRI

  • In CJD, is characteristic for bilateral areas of increased signal intensity, predominantly in the caudate and putamen

  • In sCJD,

    • Bilateral areas of increased signal intensity, ...